RARE DISEASE
Inherited arrhythmogenic cardiomyopathy
Inherited arrhythmogenic cardiomyopathy
Inherited arrhythmogenic cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Synonyms: Arrhythmogenic right ventricular cardiomyopathy
Drug discovery
4
drugs
With orphan designations
Overview
Inherited arrhythmogenic cardiomyopathy (ACM) is a genetic disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, predisposing to life-threatening ventricular arrhythmias and sudden cardiac death. Primarily affecting the right ventricle (ARVC), it can also involve the left (ALVC) or both ventricles. Desmosomal gene mutations (e.g., PKP2, DSG2) are implicated in ~50% of cases, with autosomal dominant inheritance and variable penetrance. Clinical features include palpitations, syncope, and heart failure, often manifesting in adolescence or young adulthood [1][2][6][19].
Burden
Leads to sudden cardiac death in ~2–5% of cases annually, often in young individuals/athletes [1][18].
Economic strain from ICD costs, genetic testing, and lifelong surveillance; psychological impacts on families [9][14].
Progressive heart failure necessitates transplantation in 5–10% of advanced cases [3][13].
Therapies
Risk stratification: Implantable cardioverter-defibrillators (ICDs) for high-risk patients (e.g., survivors of cardiac arrest, severe ventricular dysfunction) [3][17].
Antiarrhythmics: β-blockers (first-line), amiodarone, or flecainide for symptomatic ventricular arrhythmias [3][8][17].
Ablation: Combined endo-/epicardial catheter ablation for recurrent ventricular tachycardia [8][13].
Lifestyle: Strict exercise restriction to mitigate disease progression [2][8][18].
Categories: rare cardiac diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
707 drug discovery papers related to Inherited arrhythmogenic cardiomyopathy, with 5 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
707 drug discovery papers related to Inherited arrhythmogenic cardiomyopathy, with 5 first-in-class and 2 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-08 | Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy.
Inherited PLN (phospholamban) R14del variants cause dilated cardiomyopathy with a high burden of malignant ventricular arrhythmias. However, the single-cell electrophysiological substrate underlying arrhythmogenicity is incompletely characterized, and it is unclear whether antiarrhythmic agents validated in wild-type (WT) or long QT models retain efficacy in this genotype. We sought to define the genotype-specific electrophysiological phenotype of PLN R14del cardiomyocytes and evaluate how modulation of the transient outward potassium current and late sodium current alters arrhythmic risk. Isogenic WT (HD.15S1) and CRISPR (clustered regularly interspaced short palindromic repeats)-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes were studied using high-throughput optical action potential (AP) recordings. A deep learning framework classified AP morphology to quantify normal versus aberrant AP types, AP duration, and early afterdepolarization incidence at baseline and under graded concentrations of the transient outward potassium current activator NS-5806, the transient outward potassium current inhibitor acacetin, and the selective late sodium current blocker GS-967 (eleclazine). At baseline, PLN R14del human induced pluripotent stem cell-derived cardiomyocytes exhibited a subtle but significant arrhythmogenic phenotype, with a reduced proportion of normal APs, prolonged AP duration, and increased early afterdepolarizations compared with isogenic WT, consistent with impaired calcium handling and diminished repolarization reserve. In WT cells, NS-5806 produced a biphasic, dose-dependent response, transiently destabilizing and then restoring normal AP morphology; in PLN R14del cells, NS-5806 induced marked proarrhythmic remodeling and near-complete loss of normal APs at higher doses. GS-967 paradoxically exacerbated arrhythmic features in the mutant line, including AP duration prolongation and suppression of normal APs. Acacetin preserved stability in WT cells but failed to rescue normal AP morphology in PLN R14del cardiomyocytes. PLN R14del cardiomyopathy creates a distinct electrophysiological substrate that fundamentally alters antiarrhythmic drug responsiveness, such that agents beneficial in WT contexts may be ineffective or proarrhythmic in this genotype. Preclinical antiarrhythmic evaluation should incorporate genotype-specific, patient-derived human induced pluripotent stem cell models to enable precision medicine strategies in inherited cardiomyopathies.
2026-06-29 | TGF-β2 signaling promotes cardiac fibrosis in arrhythmogenic right ventricular cardiomyopathy mediated by DSC2 deficiency.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.
2026-06-27 | Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
2026-07-08 | Genotype-Specific Electrophysiological Remodeling in PLN R14del Cardiomyopathy: Implications for Precision Antiarrhythmic Therapy.
Inherited PLN (phospholamban) R14del variants cause dilated cardiomyopathy with a high burden of malignant ventricular arrhythmias. However, the single-cell electrophysiological substrate underlying arrhythmogenicity is incompletely characterized, and it is unclear whether antiarrhythmic agents validated in wild-type (WT) or long QT models retain efficacy in this genotype. We sought to define the genotype-specific electrophysiological phenotype of PLN R14del cardiomyocytes and evaluate how modulation of the transient outward potassium current and late sodium current alters arrhythmic risk. Isogenic WT (HD.15S1) and CRISPR (clustered regularly interspaced short palindromic repeats)-edited PLN R14del human induced pluripotent stem cell-derived cardiomyocytes were studied using high-throughput optical action potential (AP) recordings. A deep learning framework classified AP morphology to quantify normal versus aberrant AP types, AP duration, and early afterdepolarization incidence at baseline and under graded concentrations of the transient outward potassium current activator NS-5806, the transient outward potassium current inhibitor acacetin, and the selective late sodium current blocker GS-967 (eleclazine). At baseline, PLN R14del human induced pluripotent stem cell-derived cardiomyocytes exhibited a subtle but significant arrhythmogenic phenotype, with a reduced proportion of normal APs, prolonged AP duration, and increased early afterdepolarizations compared with isogenic WT, consistent with impaired calcium handling and diminished repolarization reserve. In WT cells, NS-5806 produced a biphasic, dose-dependent response, transiently destabilizing and then restoring normal AP morphology; in PLN R14del cells, NS-5806 induced marked proarrhythmic remodeling and near-complete loss of normal APs at higher doses. GS-967 paradoxically exacerbated arrhythmic features in the mutant line, including AP duration prolongation and suppression of normal APs. Acacetin preserved stability in WT cells but failed to rescue normal AP morphology in PLN R14del cardiomyocytes. PLN R14del cardiomyopathy creates a distinct electrophysiological substrate that fundamentally alters antiarrhythmic drug responsiveness, such that agents beneficial in WT contexts may be ineffective or proarrhythmic in this genotype. Preclinical antiarrhythmic evaluation should incorporate genotype-specific, patient-derived human induced pluripotent stem cell models to enable precision medicine strategies in inherited cardiomyopathies.
2026-06-29 | TGF-β2 signaling promotes cardiac fibrosis in arrhythmogenic right ventricular cardiomyopathy mediated by DSC2 deficiency.
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.
2026-06-27 | Desmoglein-2 Deficiency Drives Mitochondrial Morphological Remodeling in Cardiomyocytes.
Pathogenic variants in desmoglein-2 (DSG2) are a major cause of arrhythmogenic cardiomyopathy (ACM), a disease plagued by ventricular arrhythmias, contractile dysfunction, myocardial inflammation, and fibrofatty remodeling. Additionally, increasing evidence implicates mitochondrial dysfunction in DSG2-associated disease. However, whether mitochondrial remodeling occurs uniformly across ventricles remains less well defined. Here, we utilized a homozygous Dsg2 mutant (Dsg2mut/mut) mouse to define chamber-specific mitochondrial remodeling in DSG2-linked ACM. Re-analysis of our previously generated cardiomyocyte snRNAseq dataset revealed broad downregulation of mitochondrial transcripts involved in fusion/fission dynamics, calcium handling, mitophagy, structural organization, and electron transport chain (ETC) assembly, findings that are consistent with impaired mitochondrial homeostasis and bioenergetic capacity. Ultrastructural analyses by transmission electron microscopy showed that Dsg2mut/mut hearts contained an increased number of mitochondria, which were smaller, irregularly shaped, and more disorganized than wildtype (WT) counterparts. Importantly, these alterations were chamber-dependent, with the right ventricle (RV) displaying more pronounced reductions in mitochondrial circularity and greater mitochxondrial abundance than the left ventricle (LV), indicating increased RV susceptibility. Together, these findings unveil mitochondrial remodeling as a feature of DSG2-deficiency and support a desmosomal-mitochondrial axis in ACM pathogenesis, further supporting mitochondrial pathways as candidate therapeutic targets.
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Drug Discovery Landscape
4 orphan drug designations for Inherited arrhythmogenic cardiomyopathy.
4 orphan drug designations for Inherited arrhythmogenic cardiomyopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Atibuclimab | antibodies | FDA | 2023-09-21 | — | Implicit Bioscience Ltd. |
Adeno-associated virus vector serotype 9 containing the PKP2 gene | gene therapies | EMA | 2023-08-16 | — | Yes Pharmaceutical Development Services GmbH |
Adeno-associated virus serotype rh.74 vector containing the human Plakophilin-2a transgene (AAVrh.74-PKP2a) | gene therapies | FDA | 2023-06-05 | — | Rocket Pharmaceuticals, Inc. |
A native AAV9 capsid with a genomic cassette containing a cardiomyocyte-specific promoter and the wild-type human PKP2 gene | gene therapies | FDA | 2022-11-22 | — | Tenaya Therapeutics |
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